Spironolactone Underused, Isotretinoin Overmonitored

Current controversies in acne treatment include underutilization of spironolactone in women and the overmonitoring of patients on isotretinoin, according to William James, MD, who spoke at the American Academy of Dermatology Virtual Meeting Experience 2021, held virtually in April.

Spironolactone Myths vs Reality

Spironolactone exerts antiandrogenic effects by reducing testosterone levels and blocking male hormone effects on the skin. “However, it’s still underutilized, despite recommendations to decrease the use of antibiotics,”¹ said James, the Paul R. Gross Professor of Dermatology at University of Pennsylvania Perelman School of Medicine in Philadelphia.

William James, MD

A review coauthored by James showed that dermatologists were prescribing antibiotics for acne at roughly the same rate in 2013 as in 2004.² Meanwhile, spironolactone use grew modestly, to 8 courses per 1000 women. 

Some dermatologists may be hesitant to prescribe spironolactone to both men and women because it is not approved by the FDA for acne. The drug is approved for many other conditions, including as a treatment for heart failure and edema, James said. “However, we use many drugs that are off-label,” he noted.

Concerns include the lack of evidence supporting the use of spironolactone for acne. However, since 2017, 5 retrospective reviews involving nearly 1500 patients have shown that 80% to 85% of women with acne on spironolactone achieved clearance or near clearance.^3-7 Similarly, a review of 403 patients treated at Penn Dermatology Perelman revealed similar success rates for facial, truncal, and back acne, with no resistance over time.⁸ 

Additional concerns include spironolactone’s black-box warning regarding cancer. However, studies published during the past decade have shown no increased risk of breast cancer—even in women with a history of breast cancer—endocrine cancer, or any other cancers.^9,10 

Similarly, James said, concerns over the need to monitor for potassium increases to prevent hyperkalemia have been answered to his satisfaction.¹¹ He recommends screening for patients with histories of cardiac or renal disease or hypertension, which rarely occur in young women. 

“There’s no need to monitor potassium in most women,” he said. For women with hypertension, he coordinates with their primary care providers and monitors potassium.

A study of spironolactone in women aged 45 to 65 years showed that some experienced mild potassium elevations but remained asymptomatic.¹² “I treat older patients, and I don’t routinely check their potassium,” he said. When using antibiotics with spironolactone, James avoids trimethoprim/sulfamethoxazole, which can increase potassium levels.

Perhaps the major reason for dermatologists’ hesitation in prescribing spironolactone for women with acne, he said, is that many dermatologists lack training in this approach. 

Typical dosing ranges from 50 to 200 mg daily. “I used to start at 50 mg daily. And at 3 months, I was somewhat disappointed in the response,” he said. “I started [prescribing] 100 mg nightly many years ago and find it to be very helpful.” After 3 months on this dose, approximately 40% of women report clearance.3 Patients had few adverse effects, James added.

The most common spironolactone adverse effect involves menstrual irregularities, which affect approximately 22% of patients taking the drug.¹³ Because these irregularities are highly dose-dependent, he said, reducing dosage usually helps. Physicians can control menstrual irregularities with combined oral contraceptives (COCs), which also combat acne, or hormonal intrauterine devices, James noted.

Breast tenderness affects approximately 17% of patients and rarely causes drug discontinuation, he said. Some patients worry about hypotension, James said, which many young, otherwise healthy women have at baseline. “But in my experience, these patients don’t have problems with that,” he said.

Diuresis is rare, affecting less than 5% of patients. “A little bit of dizziness can occur with dosing, especially in the first week or 10 days. That’s why I prescribe it in the evening,” he said.

As spironolactone is an FDA category C drug, James counsels women against pregnancy while taking it. “This is only expert opinion, but I tell [couples considering conceiving] to stop spironolactone when they stop their birth control,” he said.

Canrenone, the active metabolite of spironolactone, has been found in breast milk at a minuscule fraction of the maternal dose, James said. “However, the American Association of Physicians and the World Health Organization both deem spironolactone compatible with lactation,” he said.

Women with acne often ask how long they will need to be on spironolactone. Because spironolactone merely suppresses acne, James said, patients who discontinue or reduce dosing often experience recurrences. “I emphasize that this medicine was developed for hypertension. It was made for long-term use, and there’s a lot of experience of people taking it for many years,” he said.

Typically, James prescribes spironolactone as primary treatment for all women with acne—not just those with lower-face acne or acne that flares with menstruation. He also prescribes it for women whose acne resists antibiotics or COCs or returns after successful isotretinoin use. Spironolactone also works well for patients with skin of color who are worried about postinflammatory hyperpigmentation, he said.

“When you really want to get somebody under excellent control, without any pimples or active inflammatory lesions, spironolactone is an excellent option. Because of this—and the ability to prescribe oral contraceptives—I rarely use antibiotics in women anymore,” James said.

Figure 1

Isotretinoin Hypervigilance?

Changes detected by routine laboratory monitoring of patients on isotretinoin rarely alter treatment, said John S. Barbieri, MD, MBA, a postdoctoral research fellow at the Perelman School of Medicine. He recommends limited monitoring in most cases.¹⁴

Laboratory monitoring seeks to avoid serious isotretinoin-related adverse events such as hepatotoxicity and pancreatitis while also guiding dosing. “But there are downsides. There’s the pain of getting the lab draw. There’s fear; when I tell patients they need to get blood work, they think, ‘Is this drug safe?’” he said. With high-deductible health plans, Barbieri adds, patients must cover significant lab-monitoring costs.

John Barbieri, MD, MBA

“Despite evidence that we should consider reducing our lab monitoring, it still remains common,” Barbieri said. According to results of a study of monitoring patterns between 2008 and 2017, 40% to 60% of patients on isotretinoin still undergo monthly white blood cell (WBC) and platelet counts, plus lipid tests and liver function tests (LFTs).¹⁵

“Lipid and triglyceride abnormalities are probably some of the most common issues we think about in patients treated with isotretinoin,” Barbieri, who was a coauthor of the study, said. In a chart review of 1863 patients, triglyceride and cholesterol changes plateaued after 2 to 3 months.15 “If you’re not having a problem by month 3 or peak dose, you’re probably not going to [have] one later on,” he said. Similarly, investigators observed no population-level effects on aspartate aminotransferase (AST), alanine transaminase (ALT), platelets, or WBC counts.

“What we really care about are abnormalities that might make us change treatment,” Barbieri said. Serious cholesterol increases were rare and triglyceride levels over 500 mg/dL affected 0.3% of patients in the study. “But of these patients, three-fourths continued their course of isotretinoin,” he said.

Similarly, clinically significant LFT changes affected only 1.2% of study patients. These LFT alterations were just as common at baseline as on treatment, he said. The fact that investigators did not observe an increased rate of LFT changes during treatment suggests that the abnormalities were unrelated to treatment. 

The findings mirror those of a prior Pennsylvania State University study whose authors proposed checking labs only at baseline and peak dose.¹⁶ “If no abnormalities are detected,” Barbieri said, “continue therapy with no other lab monitoring.”

In a subsequent 735-patient study, investigators found that 139 had baseline laboratory abnormalities.¹⁷ However, those abnormalities did not alter treatment. Nor did they predict which patients would develop future abnormalities. 

In a review of all pancreatitis cases arising during isotretinoin therapy, only 4 of 25 total were considered related to hypertriglyceridemia.¹⁸ “Pancreatitis absolutely can happen on isotretinoin. It’s something we should counsel our patients about,” Barbieri said, noting that patients who experience symptoms suspicious for pancreatitis should stop isotretinoin and undergo evaluation. However, he added, having only 4 of 25 cases related to hypertriglyceridemia suggests that many of the pancreatitis cases likely were idiosyncratic rather than mediated by hypertriglyceridemia.

Approximately 25% of patients on higher isotretinoin doses experience muscle aches. “Should we be checking creatinine phosphokinase (CPK) to look for those rare patients who get rhabdomyolysis?” Barbieri asked. “When we look at the data, 5% to 40% of patients might have mild CPK elevations if you check it routinely.”¹⁹ For context, athletes can have baseline CPK in the range of 500 to 1000 IU/L, which is 2 to 4 times the upper normal limit, without problems.19 Conversely, patients on isotretinoin who experience severe CPK elevations typically have severe muscle aches and other symptoms.

“Currently, there are no guidelines about how to proceed,” Barbieri said. “When it comes to my practice, I consider checking CPK in the setting of symptoms. But it’s not something that I check routinely. You’re just going to be making yourself and the patient nervous about mild, asymptomatic, nonclinically significant elevations that are more likely related to normal activities of our patients than isotretinoin.”

Based on data from his group and others, Barbieri said he hopes to convince dermatologists that “there’s no value to routine complete blood cell count, white blood cell count, or platelet testing.”

“American Academy of Dermatology guidelines don’t support monitoring complete blood counts,”²⁰ he said.

Barbieri still checks baseline labs for many patients because he believes data are insufficient to support eliminating this practice. “But we should evaluate if it’s worth it for patients because it doesn’t tend to change [treatment]. When it comes to monitoring labs, my current practice is to repeat these labs either at 2 months or peak dose,” he said. “And if they’re unremarkable at peak dose, I don’t do any further checking.”

In the United States, checking labs only at baseline and peak dose would save $17.4 million annually.¹⁵ “Those are meaningful savings for patients and the health system,” Barbieri said. “Those are meaningful improvements in quality of life.”

Minimizing monitoring also would reduce patients’ fear of isotretinoin, he added. “It’s an incredibly valuable treatment for our patients with acne, and we don’t want them to be afraid of it if they are appropriate candidates.”

Disclosures:

James and Barbieri report no relevant conflicts of interest.

References:

1. James WD. Spironolactone issues and use in acne. Presented at American Academy of Dermatology VMX; April 23-25, 2021; virtual.

2. Barbieri JS, James WD, Margolis DJ. Trends in prescribing behavior of systemic agents used in the treatment of acne among dermatologists and nondermatologists: a retrospective analysis, 2004-2013. J Am Acad Dermatol. 2017;77(3):456-463.e4. doi:10.1016/j.jaad.2017.04.016

3. Charny JW, Choi JK, James WD. Spironolactone for the treatment of acne in women, a retrospective study of 110 patients. Int J Womens Dermatol. 2017;3(2):111-115. doi:10.1016/j.ijwd.2016.12.002

4. Isvy-Joubert A, Nguyen JM, Gaultier A, et al. Adult female acne treated with spironolactone: a retrospective data review of 70 cases. Eur J Dermatol. 2017;27(4):393-398.

5. Grandhi R, Alikhan A. Spironolactone for the treatment of acne: a 4-year retrospective study. Dermatology. 2017;233(2-3):141-144. doi: 10.1159/000471799

6. Roberts EE, Nowsheen S, Davis MDP, et al. Treatment of acne with spironolactone: a retrospective review of 395 adult patients at Mayo Clinic, 2007-2017. J Eur Acad Dermatol Venereol. 2020;34(9):2106-2110. doi: 10.1111/jdv.16302

7. Barbieri JS, Choi JK, James WD, Margolis DJ. Real-world drug usage survival of spironolactone versus oral antibiotics for the management of female patients with acne. J Am Acad Dermatol. 2019;81(3):848-851. doi: 10.1016/j.jaad.2019.03.036

8. Garg V, Choi JK, James WD, Barbieri JS. Long-term use of spironolactone for acne in women: a case series of 403 patients. J Am Acad Dermatol. 2021;84(5):1348-1355. doi: 10.1016/j.jaad.2020.12.071

9. Rozner RN, Freites-Martinez A, Shapiro J, Geer EB, Goldfarb S, Lacouture ME. Safety of 5α-reductase inhibitors and spironolactone in breast cancer patients receiving endocrine therapies. Breast Cancer Res Treat. 2019;174(1):15-26. doi: 10.1007/s10549-018-4996-3

10. Wei C, Bovonratwet P, Gu A, Moawad G, Silverberg JI, Friedman AJ. Spironolactone use does not increase the risk of female breast cancer recurrence: a retrospective analysis. J Am Acad Dermatol. 2020;83(4):1021-1027. doi: 10.1016/j.jaad.2020.05.081

11. Plovanich M, Weng QY, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol. 2015;151(9):941-944. doi: 10.1001/jamadermatol.2015.34

12. Thiede RM, Rastogi S, Nardone B, et al. Hyperkalemia in women with acne exposed to oral spironolactone: a retrospective study from the RADAR (Research on Adverse Drug Events and Reports) program. Int J Womens Dermatol. 2019;5(3):155-157. doi: 10.1016/j.ijwd.2019.04.024

13. Shaw JC, White LE. Long-term safety of spironolactone in acne: results of an 8-year followup study. J Cutan Med Surg. 2002;6(6):541-545. doi: 10.1007/s10227-001-0152-4

14. Barbieri JS. Managing isotretinoin side effects: are we overmonitoring? Presented at: American Academy of Dermatology VMX; April 23-25, 2021; virtual.

15. Barbieri JS, Shin DB, Wang S, Margolis DJ, Takeshita J. The clinical utility of laboratory monitoring during isotretinoin therapy for acne and changes to monitoring practices over time. J Am Acad Dermatol. 2020;82(1):72-79. doi: 10.1016/j.jaad.2019.06.025

16. Hansen TJ, Lucking S, Miller JJ, Kirby JS, Thiboutot DM, Zaenglein AL. Standardized laboratory monitoring with use of isotretinoin in acne. J Am Acad Dermatol. 2016;75(2):323-328. doi: 10.1016/j.jaad.2016.03.019

17. Tkachenko E, Sharma P, Mostaghimi A. Abnormal baseline lab results rarely lead to treatment modification for patients on isotretinoin. Dermatology. 2020;236(6):517-520. doi: 10.1159/000505451

18. Opel D, Kramer ON, Chevalier M, Bigby M, Albrecht J. Not every patient needs a triglyceride check, but all can get pancreatitis: a systematic review and clinical characterization of isotretinoin-associated pancreatitis. Br J Dermatol. 2017;177(4):960-966. doi: 10.1111/bjd.15207

19. Marson JW, Baldwin HE. The creatine kinase conundrum: a reappraisal of the association of isotretinoin, creatine kinase, and rhabdomyolysis. Int J Dermatol. 2020;59(3):279-283. doi: 10.1111/ijd.14758

20. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-973. doi: 10.1111/ijd.14758